Employing CRISPRCas9 screen targeting chromatin regulators illuminate that SIRT6 haploinsufficiency could upregulate IGFBP2 expression level as well as attenuate sensitivity to MAPKi, and thereby enhancing BRAFV600E melanoma cell survival via triggering IGF-1R/AKT signaling pathway. The gene discussed is SIRT6; the disease is melanoma.